Efavirenz and the brain: are we nearer to solving a mysterious side-effect?

Gus Cairns

Published: 22 October 2012

One of the
most potent HIV drugs, efavirenz,
unfortunately also causes mysterious and sometimes chronic disruptions of mood,
thought and sleep. Researchers may have found the key to these side-effects,1
and evidence that the drug may contribute to the subtle deficits in brain
function usually attributed to HIV.

As Sustiva or Stocrin, or in the once-a-day pill Atripla, efavirenz is a staple part of many people’s antiretroviral
therapy (ART): in London
last year, 53% of all people on ART took it. Yet ever since its introduction in
1999, the drug has been linked to vivid dreams, poor sleep, dizziness, lack of
concentration and, in some cases, mood swings, anxiety and depression.2

It’s
accepted that these effects are common in the first month or so on the drug.
What’s disputed is whether these persist and, if so, whether they have real
impact. While some studies found no evidence for long-term side-effects,3
others did4,5 – and some found that, even in people who had
tolerated efavirenz for years, changing to other drugs, within6 or
outside7 the NNRTI class, resulted in improvements in mood.

Early
studies found that only 6% of people stopped efavirenz in the first year8
but a more recent study9 found that as many as 20% of people taking Atripla (efavirenz/tenofovir/FTC) stop
taking it within a year, largely due to psychological side-effects.

There have
been very few randomised, controlled studies to assess the extent to which
these side-effects are peculiar to efavirenz, or which can provide any
information about whether some of these effects might be due to HIV infection
itself. One of these few10 found that people on efavirenz had slower
reaction times and poorer decision-making skills than people on protease
inhibitors. But most research has been in studies where participants knew they
were on efavirenz – and the reputation of the drug is such that they may have
blamed mental distress on efavirenz when it in fact had another cause.

The picture
gets more complicated if you factor in HIV-associated neurocognitive disorder
(HAND). This is the complex of deficits in mental performance that has been
associated with HIV infection; it too tends to include deterioration of memory,
co-ordination and concentration.

Marked
brain impairment in people with HIV not taking antiretroviral therapy (ART)
usually gets better if they start ART, but the mild version of HAND often
persists. Some studies have found that people taking efavirenz have poorer HAND
scores11 and others have found that HAND may improve less in people
taking efavirenz.12

Although
mental disturbance, including psychosis and mania, has been linked to
exceptionally high efavirenz levels,13 ,14 other studies have found
no link with levels of efavirenz in blood.15 But higher drug levels
and lower HIV viral load in the cerebrospinal fluid (CSF) that surrounds the
brain were associated in one study with worse HAND symptoms,16 in
another with nerve cell loss,17 and, in a third, HAND symptoms
unexpectedly improved when patients stopped ARVs;18 these however
were not efavirenz-specific effects.

The new
research found that it might not be efavirenz itself that damages nerve cells
but a metabolite, a chemical
produced when the body acts on the efavirenz molecule.

In the
body, efavirenz turns into two molecules called 7- and 8-hydroxy-efavirenz. The
researchers incubated nerve cells taken from rats with efavirenz and these two
compounds and found that, while all three were toxic to nerve cells,
8-hydroxy-efavirenz (8HE) was ten times more so. This additional toxicity
appeared to have an independent mechanism; 8HE jammed open portals into nerve
cells called voltage-operated calcium channels (VOCCs). When these gateways are
breached, calcium floods into nerve cells, unleashing a burst of brain signals,
causing unpredictable effects.

With high
drug levels this led to nerve cell death, but with lower levels the cells lost
their ‘dendritic spines’: these are a nerve cell’s ‘input wires’ and mean that
the cell is less responsive to the signals reaching it. The typical level of
8HE seen in daily dosing of efavirenz is about three times the level sufficient
to denude cells of dendritic spines.

This could
explain why blood levels of efavirenz are not always related to side-effects:
people who efficiently metabolise efavirenz may have lower blood efavirenz
levels but higher peak levels of the 8HE compound.19

This
research comes at a crucial time for efavirenz. The drug will be one of the
first widely used ARVs to come off patent next year (see The generic generation). Generic efavirenz will be available
cheaply and there will be cost pressures for people to stay on it if they can,
rather than switch to costlier drugs.

The fact
that a drug harms cells in a lab dish doesn’t necessarily mean it will harm
them in the body. Clearly, this line of research needs to be extended. We need
to do the same experiments on neurones with metabolites of other drugs; we need
to relate brain function in people to levels of 8HE; and there should be
longitudinal research to look at how brain impairment improves or deteriorates
in people with HIV on and off treatment, and to try to tease apart the
symptomatic profiles of different kinds of neural damage.

Efavirenz
has long been blamed, rightly or wrongly, for a subtle but pervasive
deterioration in the quality of life of some people taking it and it would be
good to find out whether the drug’s benefits continue to outweigh this. The
question is, with less money available as ARVs become generic, who will fund
the research?

Issue 213: Autumn 2012

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